Compositions for treating infected skin and mucous membrane comprising an anti-microbial agent and an essential oil

ABSTRACT

The invention provides a composition of matter for treating infected skin and mucousal membranes, said composition comprising at least one anti-microbial drug; and at least one essential oil, in combination with a substantially, alcohol-free carrier system, said carrier being selected from a liquid carrier or a semi-solid carrier, said carrier system being selected from isotonic system and a moderately hypertonic system.

The present invention relates to a composition for treating infectedskin and mucousal membranes. More particularly, the present inventionrelates to a composition for treating microbially infected skin andmucousal membranes including the treatment of wounds and skin ulcers,comprising a mixture of at least one anti-microbial drug and at leastone essential oil, in a liquid or semi-solid carrier delivery system.Preferably said compositions are stabilized with at least one inactiveingredient or excipient which is non-cytotoxic at the concentration usedand which does not inhibit wound-healing, and which is isotonic ormoderately hypertonic.

BACKGROUND OF THE INVENTION

Multi antibiotic resistance of pathogenic bacteria is becoming anobstacle for effective infection treatment. Mucous and skin infectionsare in many cases hard to treat since they often involve multibacterial, yeast and fungal infections. Mucous and skin infections arealso commonly associated with inflammation, ulceration and bleeding.There is a need for a more complex product to provide a solution to themany factors encompassing the infected mucous or skin status andclinical manifestations.

Many of current pharmaceutical and cosmetic inactive ingredients orexcipients are harsh chemicals which are irritating to already affectedtissue and inhibit wound healing and new tissue generation by denaturinggrowth factors involved in tissue healing or are cytotoxic to thefibroblasts or keratinocytes.

Mucositis, Vaginitis, Anal fissure, Pressure sores, Dermatitis, Otitis,Gingivitis and Periodontitis and skin ulcers, are all prone tomulti-microbial infection and inflammation, and involve difficult tocure conditions, because of the enormous number of germs in the affectedarea.

There is a need for products that will have good anti-microbialactivity, that will simultaneously affect bacteria, yeast, fungi andviruses, that will not be susceptible to bacterial resistance and willbe innocuous to affected tissue, and which will not inhibit the naturalwound healing process.

Mucositis

Mucositis is an inflammation and ulceration of the lining of the mouth,throat or gastrointestinal tract most commonly associated withchemotherapy or radiotherapy for cancer.

Common manifestations of mucositis include ulcerations, redness, andswelling in the mouth as well as cramping, diarrhea and bleeding. Inmore severe cases, mucositis can be extremely painful, preventing thepatient from eating and necessitating hospitalization for hydration,narcotic pain medication, and/or total parenteral nutrition. Thedestruction of the protective mucous membrane can also place the patientat a serious risk of infection.

The consequences of mucositis can be significant. Mucositis is often adose-limiting toxicity of chemotherapy and radiation therapy, leading toreductions or delays in chemotherapy or irradiation doses. Dose-limitingtoxicities such as mucositis are a major concern for oncologists becausethey adversely impact the curative potential of the patient's primarytherapy. In addition, mucositis may lead to dehydration, malnutrition,or infection, all of which compromise the desired treatment plan.

There are presently no pharmaceutical agents available on the market toprevent or treat mucositis. Severe mucositis necessitates a delay in thechemotherapy schedule or reduction of the dose as well as treatment ofcomplications such as pain, dehydration, malnutrition, and infection.

Unmet needs in the area of mucositis include therapies that prevent orreduce the severity, duration, and symptoms of mucositis so thepatient's chemotherapy or radiation regimen can be maintained orintensified. Clinicians also desire a therapy that reduceshospitalization, narcotic use, or the need for nutritional support.

Vaginitis

The three most common vaginal infections are: Bacterial vaginosis,Candidiasis, or “yeast infection” and Trichomoniasis. It is common thatmore than one infection is present.

Anal Fissure

Anal fissure tends to become ulcerated or infected because of theenormous number of germs in this area; an anal fissure will always getinfected, so there is local inflammation.

An anal fissure is a superficial linear tear in the anoderm mostcommonly caused by passage of a large, hard stool. This tear is distalto the dentate line. Anal fissures are among the most common anorectaldisorders in the pediatric population; however, adults also areaffected.

The majority of anal fistulas originate in anal crypts, which becomeinfected with abscess formation. When the abscess is opened or ruptures,a fistula is formed.

Skin Ulcers

A contaminated wound will heal, an infected wound will not. Stage 2, 3and 4 pressure ulcers should all be considered as colonized withbacteria. Infected skin ulcer may result from pressure, arterialinsufficiency, venous stasis, diabetic, traumatic or burns.

Pressure Sores

Pressure sores that become infected heal more slowly and can spread adangerous infection to the rest of the body.

The antibiotic for pressure sores should be effective againstgram-negative, gram-positive, and anaerobic organisms (e.g., silversulfadiazine, triple antibiotic). Monitoring allergic sensitization andother adverse reactions is necessary due to many non-curing situations.

Oral Ulcers

There is essentially no known cause or cure of intra-oral ulcers. Theseulcers can be extremely painful to patients, and generally persist forseven to ten days. While the etiologies of oral aphthae, or cankersores, are quite varied, the central concern is the severe pain theycause. This pain affects the quality of life for millions ofindividuals. It, is believed that the pain related to the oralulcerative lesions is made more severe by the secondary infectionscaused by the prevailing oral bacteria.

One currently used common treatment for intra-oral ulcers is the use ofacyclovir, an antiviral agent effective in treatment of certain forms ofherpes. Acyclovir is available from Glaxo Wellcome under the tradenameZovirax. Zovirax consists essentially of acyclovir in a polyethyleneglycol base and is available as an ointment or rinse. This productapproaches the problem of ulcers based on the hypothesis that suchulcers or lesions are viral in nature. Another recent treatment is useof a product called Aphthasol, available from the Block Drug Company.Aphtasol consists of amlexanox, an antihistamine, in an adhesive paste.This treatment is based on the hypothesis that oral ulcers and lesionsare caused by an autoimmune or allergic response of the body. However,none of the above products has proven to be effective in reliablyreducing the pain associated with the ulcer while simultaneouslyspeeding the healing process and preventing secondary infections.

Gingivitis

Gingivitis is a disorder involving inflammation of the gums. Gingivitisis caused by the long-term effects of plaque deposits. Plaque is thesticky material that develops on the exposed portions of the teeth,consisting of material such as bacteria, mucus, and food debris. It is amajor cause of dental caries. Un-removed plaque mineralizes into a harddeposit called calculus (tartar) that becomes trapped at the base of thetooth. Plaque and calculus cause mechanical irritation and inflammationof the gingiva. Bacteria, and the toxins produced by the bacteria, causethe gums to become infected, swollen, and tender.

Severe gingivitis conditions end up in finally acute necrotizingulcerative gingivitis, Which can be life threatening.

The goal of treatment is reduction of gingival inflammation. Daily oralhygiene may include tooth brushing and oral rinse. Common toothpastesand mouth rinses comprise antiseptic agents such as Chlohexidine, Cetylpyridinium chloride, Essential oils such as Menthol, Thymol,Methylsalycilate and Eucaliptol, usually in a hydro-alcoholic solventcarrier. Commercial mouth rinses are hypertonic or contain significantconcentration of gingivitis inhibiting agents or compositions.

It is an object of the present invention to provide effectiveanti-septic and anti-bacterial composition that does not comprisesingredients that inhibit gingival healing process and do not inhibitinflammation recovery.

Periodontitis

Periodontitis is a dental disorder that results from progression ofgingivitis, involving inflammation and infection of the ligaments andbones that support the teeth. Besides dentist intervention,periodontitis is treated by application of anti-bacterial agents such asChlohexidine and Metronidazole, directly into periodontal pockets.

Otitis

Acute otitis media (OM) is a middle ear infection that may cause achange in the normal eardrum, which is located at the inner end of theear canal. Otitis externa (OE) is an infection of the outside ear canaland/or opening to the ear and is commonly called “swimmer's ear.”

In OM, the infection can be caused by a virus or by bacteria. It mayalso be accompanied by allergies, enlarged adenoids, or a cold thatcauses blockage of the eustachian tube (the connection between thethroat and middle ear that equalizes pressure).

In OE, the infection is often caused by scratching, inserting objectsinto the ear canal, or moisture, such as pool water. OE may also becaused by bacteria or fungi.

Dermatitis

Dermatitis is an inflammation of the dermis and epidermis (the skin).Symptoms include a rash, blisters, sores, lesions, itching or crackedskin. The term eczema is also used for this condition.

U.S. Pat. No. 5,213,615 discloses a dental material for the control ofcaries and paradentitis, which contains an active agent combination ofthymol and/or carvacrol and chlorhexidine and/or the physiologicallycompatible salts thereof. The dental material can be a dental varnish ora material such as a dental cement and the like, which remains in theoral cavity for a long period and from which the active combination candiffuse out.

U.S. Pat. No. 4,693,888 discloses “a caries-preventive compositioncomprises an antibody obtained by immunizing a mammal with at least oneantigen selected from the group consisting of Streptococcus mutans, itscell-wall fraction, fibrous substance fraction, glucosyltransferasefraction and protein antigen fraction, and a synergist selected from thegroup consisting of fluorine compounds, chlorhexidine and its salts,lytic enzymes, bacteriocins, glucosyltransferase inhibitors, proteasesand dextranases”.

U.S. Pat. No. 6,352,711 discloses pharmaceutical compositions whichcomprise of an effective amounts of antimicrobials, anti-inflammatories,and antihistamines, to provide an ulcer medication which preventssecondary infections and promotes healing while providing immediaterelief from pain. The composition may be used to treat a variety ofulcers including but not limited to intraoral aphthous ulcers andnon-oral lesions.

U.S. Pat. No. 6,387,352 states that “Although chlorhexidine has beenshown to be useful in the prevention of bacterial and fungal infection,there are no consistent findings in the value of chlorhexidine inreducing mucositis in cancer patients. It probably works on thesecondary microbial initiation of already-affected tissue. The problemwith its use is that, once mucositis starts, the alcohol content ofchlorhexidine preparations makes it difficult for the patient to useeven at one-half strength. It is difficult to force the patients who areexperiencing severe pain and who are already on morphine to usesomething that increases their pain. Chlorhexidine was used as long asthe patient could tolerate it—usually until the onset of mucositis.”

U.S. Pat. No. 6,458,777 discloses administration of anti-microbialagents in combination with “inflammatory cytokine inhibitor” which“result in an even more effective method for treating and preventingmucositis”.

None of the above-mentioned patents teaches the composition ofantibiotic and essential oils for preventing or treating mucous or woundinfections.

Recent scientific data suggests that alcohol may play a role in toxicand genotoxic biological effects. Consumers are therefore refrainingfrom using products containing alcohol, especially for sensitive bodyorgans such as for the oral cavity and babies' skin. Alcohol is anirritant to the skin, scalp, mucous membrane and gastrointestine. In theoral cavity alcohol has a foul taste, which is especially unpleasant foryoung and elderly people. Alcohol burns tissues in a way that delaystissue healing after skin traumas. Alcohol dehydrates the skin, mucousmembrane and tissues, which in turn causes discomfort and pain.Therefore medical research is investing in finding alcohol freemedicaments.

Chlorhexidine, an antimicrobial mouth rinse, has also been usedextensively in the treatment and prevention of oral mucositis (Ferrettiet al., 1990, Bone Marrow Transplan. 3:483-493; Weisdorf et al., 1989,Bone Marrow Transplan. 4:89-95). It has been noted however that theefficacy of chlorhexidine is significantly decreased in saliva, and thatthis compound is relatively ineffective against the Gram negativebacteria that tend to colonize the oral cavity in patients undergoingradiation therapy (Spijkervet et al., 1990, Oral Surg. Oral Med. OralPathol. 69:444-449). In addition, at least one study has shown that theuse of chlorhexidine may be detrimental and result in a higher incidenceof mucositis (Foote et al., 1994, J. Clin Oncol. 12:2630-2633).

Several studies have shown that the use of a vancomycin paste andantibiotic lozenges containing polymixin B, tobramycin and amphotericinB in patients undergoing myelo-suppressive chemotherapy or radiationtherapy can result in a decrease in oral mucositis and in the incidenceof sepsis due to alpha hemolytic streptococci (Barker et al., 1995, J.Ped. Hem. Oncol. 17:151-155; Spijkervet et al., 1991, In: IrradiationMucositis, Munksgaard Press, pp. 43-50). Despite the clear need fortherapeutic agents to treat oral mucositis, no drugs are currentlyapproved for this indication. As a result, there is no standardtreatment for this disorder.

The present invention is based on the discovery that combinations of atleast one anti-microbial agent and at least one essential oil,formulated in a liquid or semi-solid delivery system that comprises onlysuch ingredients that are non-toxic and are not wound healinginhibitors, at the concentration used, provide unexpected and highlyeffective Mucositis and Ulcers medications.

The present invention provides a medication, which prevents and treatsinfection, inflammation, and bleeding and promotes healing whilesimultaneously providing relief from pain for infected skin and mucousalmembranes.

Moreover, in contrast to above-mentioned discussion of the harmfuleffect of chlorhexidine and its inappropriate use in mucositis, it hasnow been discovered that a mixture of chlorhexidine with essential oilsin an alcohol-free formulation is beneficial to patients suffering fromsevere mucositis; is effective for curing the infection and inflammationand for reducing pain and improving swallowing difficulties. Thealcohol-free chlorhexidine formula enables repeated usage, several timesa day, since the formula is well accepted. It has now been furtherdiscovered according to the present invention that it is possible toprepare a mouthwash formula of bitter drugs such as chlorhexidine havingimproved taste, thereby improving patient's compliance. It has also beendiscovered that a medicated mouthwash composition of matter according tothe present invention is effective in preventing and treating mucositis.

It has also been found that combining of at least one anti-bacterial oranti-septic drug with an essential oil or with a mixture of essentialoils, when formulated in a system selected from an isotonic system and amoderately hypertonic system which system is substantially free of woundhealing inhibitors and substantially free of cytotoxic agents, isunexpectedly more effective in treating external infectious conditionsof skin and mucous, such as: Otitis, Anal fissure, Dermatitis,Gingivitis, Periodontitis and Mucositis, as mentioned above.

DETAILED DESCRIPTION OF THE INVENTION

Thus, according to the present invention, there is now provided acomposition of matter for treating infected skin and mucousal membranes,said composition comprising at least one anti-microbial drug; and atleast one essential oil, in combination with a substantially,alcohol-free carrier system, said carrier being selected from a liquidcarrier or a semi-solid carrier, said carrier system being selected fromisotonic system and a moderately hypertonic system.

In preferred embodiments of the present invention, said carrier is madeof pharmaceutical or cosmetic ingredients, known to persons skilled inthe art, which are selected from stabilizing, suspending or gellingagents, that are devoid of the unwanted effects of fibroblasts andkeratocytes toxicity and wound healing inhibition and irritation at theconcentrations used at the application.

Most preferred stabilizing agents are hydrocolloids and mild non-ionicsurfactants, which cause at most only minimal hemolysis.

Hydrocolloids are hydrophilic polymers, of vegetable, animal, microbialor synthetic origin, that generally contain many hydroxyl groups and maybe polyelectrolytes. They are naturally present or added to control thefunctional properties of aqueous pharmaceutical and cosmetics. Mostimportant amongst these properties are viscosity (including thickeningand gelling) and water binding but also significant are many otherproperties, including emulsion stabilization, prevention of icere-crystallization and organoleptic properties.

Preferred hydrocolloids are selected from the group consisting ofAlginate, Cellulose and cellulose derivatives such as hydroxy methylethyl and propyl derivatives, Xanthan gum, Gum arabica, Carrageenan,Guar gum, Gelatin, Pectin, Starch, Carboxy-methylcellulose, Hyaluronicacid and Chitosan, Alginate, pullulan, polyvinyl pyrrolidone, polyvinylalcohol, dextrin, pectin, chitin, collagen, gelatin, zein, gluten,starch and starch derivatives.

Preferred mild non-ionic surfactants are Sucrose esters and Sorbitanesters such as spans.

Example of unwanted ingredients that are irritating and wound healinginhibitors are pharmaceutical solvents such as ethyl-alcohol andstabilizers such as sodium lauryl sulphate or polyoxyethylene polymersderivatives, used extensively in medicine and cosmetics, but are avoidedin the formulations and products of the present invention.

Ethanol, propylene glycol, dimethylsulfoxide, dimethylformamide, andBrij 96 have been shown to be cytotoxic to human keratinocyte andfibroblast cultures (Ponec et al. J Pharm Sci 1990 April; 79(4): 312-6)and are all inappropriate for use in the invented composition.

The anti-microbial drugs contemplated for use in the present inventionare selected from the group consisting of antibiotics, anti-fungals,anti-protozoals and anti-virals. Antibiotics include but are not limitedto: beta-lactams penicillins and cephalosporines, Macrolides,Licosamides, Aminoglicosides such as Gentamycin, Tetracyclines,Polypepetides such as Vancomycin, Sulfonamides, Flioroquinolones,chloramphenicol, nitrofurantoin and chlorhexidine. Anti-fulgalsincluding but not limited to: Nystatine, Amphotericine B, Griseofulvine,Miconazole, Itraconazole, Fluconazole, Ketoconazole, Terbinafine, SilverSulfadiazine, Flucytosine and Clotrimazole. Anti-protozoals include butarenot limited to: metronidazole, eflornithine, furazolidone,hydroxychloroquine, iodoquinol and pentamidine. Anti-virals include butare not limited to acyclovir, amantadine, famciclovir, ganciclovir,rimantadine and valacyclovir.

Antimicrobial agents are defined as organic chemicals that derive theirantimicrobial activity through a chemical or physiochemical interactionwith the microbial organisms. For example, Cetyl pyridinium chloride,triclosan, biguanides include the free bases or salts of alexidine,chlorhexidine, hexamethylene biguanides and their polymers, andcombinations of the foregoing. The salts of alexidine and chlorbexidinecan be either organic or inorganic and are typically gluconates,nitrates, acetates, phosphates, sulfates, halides and the like. Thepreferred biguanide is the hexamethylene biguanide commerciallyavailable from Zeneca, Wilmington, Del. under the trademark Cosmocil.™.CQ. Generally, the hexamethylene biguanide polymers, also referred to aspolyaminopropyl biguanide (PAPB), have molecular weights of up to about100,000.

An essential oil or volatile oil is a volatile mixture of esters,aldehydes, alcohols, ketones and terpenes, which is prepared frombotanical materials or plant cell bio-mass from cell culture. Examplesof essential oils include, but are not limited to, oil of cinnamon,prepared from the dried bark of the roots of Cinnamomum zeyloriaceae;cajeput oil, eucalyptus oil, prepared from the fresh leaves and branchesof various species of Eucalyptus, such as E. globulus; fennel oil,prepared from dried ripe fruit of Foeniculum vulgare; geranium oil,prepared from the aerial parts of Pelargonium species; girofle oil,lavander oil, prepared from fresh flowering tops of Lavandula speciessuch as Lavandula officinalis; lemon oil, obtained from the fresh peelof Citrus lemon; spearmint oil, prepared from the aboveground parts offresh flowering Mentha species, such as M. spicata; myrte oil, origanooil, pine oil, rosemary oil, prepared from tops or leafy twigs ofRosmarinus officinalis; sarriette oil, thyme oil, prepared from theleaves and flowering tops of Thymus vulgaris; and tea-tree oil, obtainedfrom the leaves of Melaleuca oltemifolia. Hypericum oil, Pinus, Staranise seeds oil, Lemon oil and Garlic oil (Allium sativum oil).

Also included in this class of essential oils are the key chemicalcomponents of the plant oils, which have been found to be the majorconstituents of the natural oil and which have in many cases identicalactivity and typical physical and chemical properties. These chemicalsinclude, but are not limited to anethol, catechole, camphene, thymol,eugenol, eucalyptol, ferulic acid, farnesol, hinokitiol, tropolone,limonene, menthol, methyl salicylate, carvacol, terpineol, verbenone,berberine, ratanhiae extract, caryophellene oxide, citronella acid,curcumin, nerolidol and geraniol.

The composition of the present invention may further include a woundhealing agent such as but not limited to Aloe vera dry extract, Herbalstannins, Echinacea extract, Comfrey extract, Allantoin, Turmeric dryextract, and recombinant growth factors. Hyaluronic acid, alginates andchitosans, which are also known to be a wound-healing agent may servedouble functions, wound healing and major vehicle stabilizing excipient.

The liquid and/or semi-solid delivery system of the present inventionmay be used as is for application on the affected disease location, orcan be provided as a concentrated formula to be diluted before use toobtain proper concentration of the bio-actives: the anti-microbial drugand the essential oil. Concentrated formulas are simpler to stabilizeand achieve long shelf life and microbiological preservation, whileproducing a non-cytotoxic and wound healing formulation upon dilutionbefore use.

Bactericidal ointments for the treatment of wounds are well known. Suchointments typically contain an antibiotic or an anti-bacterial agent inan inert vehicle or carrier, such as a paraffin base ointment or anoil-in-water emulsion. Antibiotics, which are Used, include gentamycinsulphate and neomycin sulphate, while anti-bacterial agents includecetrimide, chlorhexidine gluconate and silver sulphadiazine.

An inactive ingredient which is non-cytotoxic and which does not inhibitwound-healing is known per se and is selected from those chemical orpharmaceutical non-active ingredients used for stabilizing theformulation which do not show toxicity or killing effect to fibroblatsand keratinocytes in in-vitro culture.

Non-irritating chemicals are those that do not cause local inflammatoryreaction and which do not produce tissue destruction or irreversiblechange at the site of contact; the macroscopic manifestations ofirritation are edema and erythema. Alcohol causes moderate skinirritation. Other common irritating ingredients are ionic surfactants,microbial preservatives and non-ionic PEO surfactants.

Bacterial multiple resistance to antibiotics is a major problem inmodern medicine. Essential oils are potent anti-microbials with noreported major bacterial resistance. Combining anti-microbial drug andessential oil enables application of reduced drug concentration whilekeeping anti-microbial activity, hence improving therapeutic index andovercoming the multiple resistance problems.

Anhydrous bases are made of olefins, silicon or polyols and may beliquid or semi-solid. Examples of such polyols include, but are notrestricted to polyethylene glycol, propylene glycol, polypropyleneglycol, diethylene glycol, glycerine and ethylene glycol.

Liquid or semi-solid aqueous formulas at the final applicationconcentration may include polyols only in limited quantities that shouldnot produce cytotoxic product. High polyols concentration is possibleaccording to the current invention, in cases of products that arediluted before use, in a way that the final application product is somuch diluted as to not have cytotoxic or wound-healing inhibitioneffects.

Liquid or semi-solid compositions of the present invention may befurther packaged in plastic bottles, tubes, aluminum tubes pressurizedaerosol or foam or non pressurized aerosol or drops or glass bottles, aswell as in any other conventional packaging and closure materials. Soliddosage forms may be shaped into small unit chips for periodontal pocketinsertion or into confectionary or strips for oral mastication.

A preferred composition of the present invention is formulated inconcentrate form for subsequent dilution before use. Precise dilution isobtained by using a dosing pump or any other dosing device such asdroppers or measuring cups. A preferred method is a dual chamberpackaging wherein the concentrate is placed in one compartment and thedilution aqueous medium is placed in the second compartment and twocompartments or chambers are mixed together before use to obtain thedesired composition and concentrations of the anti-microbial drug andthe essential oil or oils composition, in an isotonic or moderatelyhypertonic product that do not comprise ingredients in concentrationsthat inhibit tissue healing.

The anti-microbial and essential oil mixture for treating mucous, woundinfections and ulcers may also contain common pharmaceutical additives,such as but not limited to; flavors or sweeteners in oral use,anti-oxidants such as vitamin E or CoenzymeQ10 or colorant oremollients, as common in the pharmaceutical art, in such concentrationthat no cytotoxic effect is present in the method of application.

The preferred anti-microbial drug concentration is dictated from itsUSP-NF monograph, the PDR or instruction for use as approved by theregulatory agencies. Concentrated formulas may have for example 10 timesthe recommended use concentration, and are diluted accordingly, 10 timesbefore use by medical team or patient, to obtain the desired drugconcentration for application.

According to the present invention, finally diluted composition which isdirectly applied onto affected area should be isotonic or of low ormoderate hyper-tonicity and not hypertonic. Examples of unwantedhypertonic compositions are: 70% Sorbitol or 10% Glycerin in finalformulation.

An isotonic solution in medicine is one that can be mixed with bodyfluids without causing any disturbance that is about 280 to 320milliosmolar. Moderate hypertonic is a solution with osmotic pressure ofless than twice the isotonic pressure and preferably not higher than 50%of isotonic solution.

Essential oils, such as Thyme, Eucalyptus and Cinnamon oils are mostpreferably used at concentrations of 0.05% to 0.5%, whereas 10 timesconcentrated formula may contain 0.5% to 5% to be diluted 10 timesbefore use to obtain desired final concentration for application.Mucositis treatment requires low essential oils concentration whileaphtouse or mouth ulcers are treated with much higher concentration.

Preferred stabilizing agents include alginate, hyaluronic acid,chitosan, acacia, xanthan gum, locust bean gum, guar gum, cellulosederivatives and gelatin and the like, in amounts ranging from about 0.01to about 10.0 wt. %, preferably about 0.2 to about 4 wt. %.

Preferred emulsifying agents include sucrose esters, sorbitan esters,polyglyceryl esters, lecithin, bentonite, veegum, and the like, inamounts ranging from about 0.01 to about 4 wt. %, preferably about 0.1to about 1.0 wt. %.

Preferred thickening agents include methylcellulose, hydroxypropylmethylcellulose, carboxy-methylcellulose, and the like, in amounts rangingfrom about 0.01 to about 10 wt. %, preferably about 0.1 to about 4 wt.%.

While the invention will now be described in connection with certainpreferred embodiments in the following examples so that aspects thereofmay be more fully understood and appreciated, it is not intended tolimit the invention to these particular embodiments. On the contrary, itis intended to cover all alternatives, modifications and equivalents asmay be included within the scope of the invention as defined by theappended claims. Thus, the following examples which include preferredembodiments will serve to illustrate the practice of this invention, itbeing understood that the particulars shown are by way of example andfor purposes of illustrative discussion of preferred embodiments of thepresent invention only and are presented in the cause of providing whatis believed to be the most useful and readily understood description offormulation procedures as well as of the principles and conceptualaspects of the invention.

EXAMPLES Example 1

INGREDIENT % w/w Chlorhexidine gluconate 20% solution 20 Thyme oil 0.5Cinammon oil 0.5 Aloe vera dry extract 0.2 Methyl cellulose 4000 4.0Sucrose ester (HLB 15) 0.6 Sweetener Stevia extract 0.1 MCT oil 10.0Glycerin To 100

This Mucositis mouthwash is a concentrated formula to be diluted withwater before use by the patient. Precise twenty times dilution withwater is enabled by using dosing pump or dual chamber device to obtainfinal Chlorhexidine gluconate concentration of 0.2%.

This Mucositis mouthwash was well tolerated even by severe mucositisdeveloped after chemotherapy and irradiation therapy. Patients use itat-libidum in contrast to the unaccepted alcoholic marketedChlorhexidine mouthwash, and report on reduced pains, improvedswallowing and faster Mucositis healing.

Example 2 Mouth Ulcers (Aphtouse) Mouthwash

INGREDIENT % w/w Acyclovir 2.0 Thyme oil 0.5 Tea Tree oil 0.5 Cinammonoil 0.5 Aloe vera dry extract 0.1 Echinacea glycerin extract 1.0Propolis 0.2 Sodium Carboxymethylcellulose 1.5 Xanthan gum 0.2 Sucroseester (HLB 15) 0.4 MCT oil 0.5 Glycerin 4.0 Water To 100

This aphtouse formula was effective in treating recurrent aphtouse(mouth ulcers) conditions, reducing pain, shortening healing period andenabling comfortable eating including acidic orange juice, within 24hour of aphtouse eruption and treatment.

Example 3 Vaginal Wash

INGREDIENT % w/w Miconazole 10.0 MCT oil 8.0 Thyme oil 0.5 Lavender oil0.5 Aloe vera dry extract 0.2 Methyl cellulose 4000 4.0 Span 80 0.8Glycerin To 100

This Vaginal wash formula should be diluted 10 times with water beforeuse. It has been found effective in treating Vaginitis of yeastinfection and well accepted.

Example 4 Vaginal Gel

INGREDIENT % w/w Metronidazole 1.0 Thyme oil 0.1 Geranium oil 0.1 Aloevera dry extract 0.1 Methyl cellulose 4000 4.0 Xantan gum 0.2 Sucroseester (HLB 15) 0.6 Water To 100

Example 5 Anal Fissure Gel

INGREDIENT % w/w Chlorhexidine gluconate 20% 0.2 Thyme oil 0.2Eucalyptus oil 0.2 Hypericum oil 0.2 Echinacea dry extract 0.2 Chamomiledry extract 0.2 Sodium Carboxymethylcellulose 1.2 Span 80 0.5 Water To100

This Anal fissure formula was effective in reducing pain, shorteninghealing period and treating anal fissures without use of steroids.

Example 6 Pressure Sore Wash

INGREDIENT % w/w Chlorhexidine gluconate 20% 10 Thyme oil 0.5 Eucalyptusoil 0.5 Aloe vera dry extract 0.2 Alginate 2.0 Sucrose ester (HLB 15)0.6 Glycerin To 100

This pressure sore formula is concentrated and should be diluted withsterile water before use to obtain 0.2% Chlorhexidine gluconate washsolution.

Example 7 Pressure Sore Dressing

INGREDIENT % w/w Chloramphenicol 1.0 Thyme oil 0.1 Eucaliptus oil 0.1Alantoin 1.0 Aloe vera dry extract 0.1 Hyaluronic acid 2.0 Sucrose ester(HLB 15) 0.2 Water To 100

Example 8 Acne Gel

INGREDIENT % w/w Tetracycline 2.0 Geranium oil 0.05 Citronella oil 0.05Aloe vera dry extract 0.1 Hyaluronic acid 0.5 Span 80 0.4 Glycerin 10.0Water To 100

Example 9 Skin Ulcer Dressing

INGREDIENT % w/w Silver sulfasalazine 1.0 Geranium oil 0.05 Thyme oil0.05 Aloe vera dry extract 0.1 Chitosan 4.0 Span 80 0.2 Water To 100

This formula proved to be effective anti-microbial treatment forinfected skin ulcers. Chitosan may require low pH for hydration.

Example 10 Ear Drops

INGREDIENT % w/w Bacitracin 1.0 Eucalyptus oil 0.25 Thyme oil 0.25 Aloevera dry extract 0.1 Hyaluronic acid 0.2 Span 80 0.2 Carbopol 980 0.6Water To 100

This ears drops formula proved to be effective anti-microbial treatmentfor infected Otitis externa and pain relief in difficult cases.

Example 11 Mouth Rinse to Treat Gingivitis

INGREDIENT % w/w Cety pyridinium chloride 2.0 Eucalyptol 3.68 Thymol2.56 Menthol 1.68 Methyl salycilate 2.4 Aloe vera dry extract 0.1Hyaluronic acid 0.2 Span 80 0.2 Pemulen TR1 0.2 MCT oil 2.0 Glycerin To100

This anti gingivitis mouth rinse formula is diluted 20 times with waterbefore use and is stable after reconstitution for couple of months andhas been proved to be effective anti-gingivitis treatment in kids,diabetics and other conditions where use of alcohol prohibited or notrecommended.

Example 12 Mouth Rinse to Treat Gingivitis

INGREDIENT % w/w Cety pyridinium chloride 2.0 Eucalyptol 0.4 Thymol 0.6Menthol 1.2 Methyl salycilate 1.0 Sucrose ester 0.8 Span 80 0.2 PemulenTR2 0.2 MCT oil 4.0 Glycerin To 100

This anti gingivitis mouth rinse formula is diluted 20 times with waterbefore use and is stable after reconstitution for couple of months.

Example 13 Mouth Rinse for Dental Plaque Control

INGREDIENT % w/w Sodium Fluoride 1.0 Eucalyptol 0.4 Thymol 0.6 Menthol1.2 Methyl salycilate 1.0 Hammamelis dry extract 0.1 Sucrose ester 0.8Pemulen TR2 0.2 MCT oil 2.0 Propylene glycol To 100

This anti gingivitis mouth rinse formula is diluted 20 times with waterbefore use and is stable after reconstitution for couple of months.

It will be evident to those skilled in the art that the invention is notlimited to the details of the foregoing illustrative examples and thatthe present invention may be embodied in other specific forms withoutdeparting from the essential attributes thereof, and it is thereforedesired that the present embodiments and examples be considered in allrespects as illustrative and not restrictive, reference being made tothe appended claims, rather than to the foregoing description, and allchanges which come within the meaning and range of equivalency of theclaims are therefore intended to be embraced therein.

1. A composition of matter for treating infected skin and mucousalmembranes, said composition comprising: a) at least one anti-microbialdrug; and b) at least one essential oil, in combination with asubstantially, alcohol-free carrier system, said carrier being selectedfrom a liquid carrier or a semi-solid carrier, said carrier system beingselected from isotonic system and a moderately hypertonic system.
 2. Acomposition according to claim 1, wherein said carrier is substantiallyfree of cytotoxic excipients and is free of excipients, which inhibitwound healing.
 3. A composition according to claim 1, wherein thecarrier is an aqueous formulation stabilized with a pharmaceutical orcosmetic excipent which does not inhibit wound healing.
 4. A compositionaccording to claim 1, wherein the carrier is an aqueous formulationstabilized with a hydrocolloid dispersing or gelling agent.
 5. Acomposition according to claim 1, wherein the carrier is an aqueousformulation stabilized with a non-ionic surface-active stabilizingagent.
 6. A composition according to claim 1, wherein the carrier is anaqueous formulation stabilized with a polysaccharide dispersing orgelling agent.
 7. A composition according to claim 1, wherein thecarrier is an aqueous formulation stabilized with a synthetic orsemi-synthetic polymer as dispersing or gelling agent.
 8. A compositionaccording to claim 1, wherein the carrier is a liquid emulsion orsuspension.
 9. A composition according to claim 1, wherein the carrieris in the form of a semi-solid selected from the group consisting of agel, an ointment and a cream.
 10. A composition according to claim 1,wherein the carrier is an anhydrous base.
 11. A composition according toclaim 1, wherein the carrier is substantially free of alcohol andsubstantially free of organic solvents.
 12. A composition according toclaim 1, wherein the carrier is substantially free of irritatingemulsifiers.
 13. A composition according to claim 1, wherein theanti-microbial agent is selected from the group consisting ofanti-bacterial drugs, anti-fungal drugs and anti-viral drugs.
 14. Acomposition according to claim 1, wherein the essential oils areselected from pharmaceutical grade essential oils.
 15. A compositionaccording to claim 1 further comprising a wound-healing agent.
 16. Acomposition according to claim 1, wherein said at least oneanti-microbial drug and said at least one essential oil are concentratedand the composition is diluted with water before use to obtain theappropriate treatment concentration.
 17. A method for preventing and ortreatment of mucous and skin infection diseases selected form the groupconsisting of Mucositis, Gingivitis, Periodontitis, Vaginitis, Analfissure, Skin ulcer, Otitis, Dermatoses comprising application of aformulation comprising at least one anti-microbial drug; and at leastone essential oil, in combination with a substantially, alcohol-freecarrier system, said carrier being selected from a liquid carrier or asemi-solid carrier, said carrier system being selected from isotonicsystem and a moderately hypertonic system.
 18. A method according toclaim 17, wherein the formulation is stabilized with a pharmaceutical orcosmetic hydrocolloid, which does not inhibit wound healing.
 19. Amethod according to claim 17, wherein the formulation is stabilized witha pharmaceutical or cosmetic non-ionic surface-active agent, which doesnot inhibit wound healing.
 20. A method according to claim 17, whereinthe active ingredients in said formation are concentrated and thecomposition is diluted before use to obtain appropriate treatmentconcentration, which is not hypertonic.